Innate immunity is the first line of defense designed to protect the host from invading pathogens, including HIV. HIV viremia is associated with a wide range of immune dysfunctions that contribute to an immunocompromised state and disease progression. Persistent HIV replication has been shown to have a broad effect on several immune cell types and/or their interactions involved in mounting an effective immune response. We have previously described several NK cell abnormalities in HIV-viremic individuals. In the past year, we investigated the integrity of plasmacytoid dendritic cell (pDC)-NK cell interactions among HIV viremic, aviremic and seronegative individuals. Our results describe: 1) a critical defect in the ability of pDCs from HIV infected individuals to secrete IFN-&#61537; and TNF and subsequently activate NK cells and: 2) an inherent defect in NK cells from HIV infected individuals to respond to pDC-secreted cytokines. Furthermore, we were able to demonstrate a direct effect of HIV trimeric gp120 on NK cells in vitro similar to that described ex vivo. Finally, we were able to establish that HIV gp120-mediated suppressive effect on NK cells resulted from its binding to the integrin alpha4beta7 expressed on NK cells. These findings suggest a novel mechanism by which HIV is capable of suppressing innate immune function in infected individuals.